Exploring the Clinical and Genetic Spectrum of Steroid Resistant Nephrotic Syndrome: The PodoNet Registry

Abstract

Background: Steroid resistant nephrotic syndrome (SRNS) is a rare condition, accounting for 10–15% of all children with idiopathic nephrotic syndrome. SRNS can be caused by genetic abnormalities or immune system dysfunction. The prognosis of SRNS varies from permanent remission to progression to end-stage kidney disease, and post-transplant recurrence is common.Objectives: The PodoNet registry project aims to explore the demographics and phenotypes of immune-mediated and genetic forms of childhood SRNS, to assess genotype-phenotype correlations, to evaluate clinical management and long-term outcomes, and to search for novel genetic entities and diagnostic and prognostic biomarkers in SRNS.Methods: In 2009, an international registry for SRNS was established to collect retro- and prospective information on renal and extrarenal disease manifestations, histopathological and genetic findings and information on family history, pharmacotherapy responsiveness and long-term outcomes. To date, more than 2,000 patients have been enrolled at 72 pediatric nephrology centers, constituting the largest pediatric SRNS cohort assembled to date.Results: In the course of the project, traditional Sanger sequencing was replaced by NGS-based gene panel screening covering over 30 podocyte-related genes complemented by whole exome sequencing. These approaches allowed to establish genetic diagnoses in 24% of the patients screened, widened the spectrum of genetic disease entities presenting with SRNS phenotype (COL4A3-5, CLCN5), and contributed to the discovery of new disease causing genes (MYOE1, PTPRO). Forty two percent of patients responded to intensified immunosuppression with complete or partial remission of proteinuria, whereas 58% turned out multi-drug resistant. Medication responsiveness was highly predictive of a favorable long-term outcome, whereas the diagnosis of genetic disease was associated with a high risk to develop end-stage renal disease during childhood. Genetic SRNS forms were generally resistant to immunosuppressive treatment, justifying to avoid such pharmacotherapies altogether once a genetic diagnosis is established. Even symptomatic anti-proteinuric treatment with RAS antagonists seems to be challenging and of limited efficacy in genetic forms of SRNS. The risk of post-transplant disease recurrence was around 30% in non-genetic SRNS whereas it is negligible in genetic cases.Conclusion: In summary, the PodoNet Registry has collected detailed clinical and genetic information in a large SRNS cohort and continues to generate fundamental insights regarding demographic and etiological disease aspects, genotype-phenotype associations, the efficacy of therapeutic strategies, and long-term patient and renal outcomes including post-transplant disease recurrence.

Serum IgG Level and IgG/IgM Ratio on Admission Predict Steroid-Resistant Response in Vietnamese Children with Idiopathic Nephrotic Syndrome

“…Steroid resistance in the children with idiopathic NS is related to many factors including the histopathological lesions. Previous studies also confirmed that primary NS in children with steroid resistance was more common in patients with FSGS, MesPGN, and MPGN (14,(25)(26)(27). These results showed a significant rate of minimal changes in nephrotic syndrome in the steroid-resistant group (28,29).…”

CoQ10-related sustained remission of proteinuria in a child with COQ6 glomerulopathy—a case report

“…Primary deficiency caused by mutations in COQ genes results in various manifestations and heterogenic symptoms from kidneys and the nervous and muscular systems [10]. Among the so far studied genes, 4: PDSS2 / COQ1 , COQ2 , COQ6 , and ADCK4 / COQ8B are associated with steroid-resistant nephrotic syndrome (SRNS)—they are mutated in about 1% of cases [2, 3]. Mutations in PDSS2 and COQ2 are also mostly associated with progressive encephalopathy, seizures, and hypertrophic cardiomyopathy, while ADCK4 disease typically manifests as an isolated nephropathy [11].…”

“…It can be hypothesised that in patients with refractory proteinuria of unknown origin early genetic screening for treatable defects such as presented could provide a highly practical tool for the therapy optimization, before the progression of kidney damage. The PodoNet consortium revealed a number of such Janus-faced genes presenting in an oligosyndromic manner (including WT1 , SMARCAL1 , ADCK4/COQ8B , COL4A3-5 , CLCN5 ), where incidental diagnosis through NGS screening allowed for identification of the causative mutation in patients lacking extrarenal manifestation(s) classically associated with the particular genetic defect [3]. …”

“…Second-line therapy is fraught with high risk of side effects and is sometimes inefficacious. There are a growing number of studies exploring the genetic background of steroid-resistant glomerulopathies [2, 3]. Reports of coenzyme Q complex defects have recently been published.…”

NUP Nephropathy: When Defective Pores Cause Leaky Glomeruli

“…2 The age at first disease manifestation and the rate of chronic kidney disease progression will strongly depend on the gene affected and the type of mutation. 3 However, posttransplantation disease recurrence, observed in one-third of patients with immune-mediated disease, does not occur in patients with genetic podocytopathies.…”